Tumor is the second largest disease after the cardiovascular disease worldwide and the tumor incidence rate is still rising in recent years. The treatment of cancer has always been a problem troubling human beings. Because of the lack of selectivity of targets, traditional chemotherapy drugs tend to produce more serious toxic side effects. This situation requires people to develop antitumor drugs of specific molecular targets with high efficiency and low toxicity. It has become an important direction of research and development of antitumor drugs nowadays to use a key enzyme of cell signal transduction pathway related to tumor cell differentiation, proliferation and metastasis as a target of drug screening, and find new anticancer medicine selectively acting on this specific target with high efficiency, low toxicity and high specificity. Histone deacetylase (HDAC) is such a key enzyme.
Multiple Sclerosis (MS) is a typical kind of typical autoimmune disease diseases. The pathology of MS disease includes acute inflammation of the central nervous system and demyelination, which is one of the most important causes leading to noninvasive paralysis of the nervous system and disability among young people. The clinical manifestation of MS is heterogeneous. More than 80% of the patients are manifested as relieved relapse phenotype. Since pathogenesis of the disease is unknown and sensitive diagnostic signs are still lacking at present, the diagnosis of MS still only depends on multiple characteristic of the disease in time and space. In addition, a lot of other diseases such as ophthalmoneuromyelitis have symptoms extremely similar to MS. Therefore, for MS treatment even the diagnosis remains very difficult at present.
The current findings indicate that CD4+ T cells play an important role in the pathogenesis of MS, at least initiating MS at an early stage. Previous studies suggest that TH1 cell (characterized in producing IFN-γ) plays an important role in the occurrence of the diseases. With the discovery of TH17, more and more evidence shows that the function of latter in the pathogenesis of MS is not inferior than that of TH1, for example, the mice with less quantity of TH17 cells were not susceptible to EAE (Experimental Autoimmune Encephalomyelitis), TH17 cells were identified in the brain tissue of the MS patients, etc.
Chromatin histone acetylation and deacetylation are critical processes regulating gene expressions, while abnormal gene expression is the molecular biological basis of the occurrence of tumor and some genetic and metabolic diseases. The degree of acetylation of histones is coordinativly controlled by histone acetyltransferase (HAT) and histone deacetylase (HDAC). When HDAC is over expressed and then recruited by a transcription factor, it will lead to the abnormal inhibition of specific genes, thus resulting in the occurrence of tumors and other diseases.
HDACs have eighteen subtypes, which can be divided into four classes, namely class I (HDAC1,2,3,8), class II (HDAC1,2,3,8), class III (SIRT1˜7) and class IV (HDAC11) respectively. (Johnstone, R. W. 2002 Nature Rev. Drug Disc. 1:287). It is reported that activity of HDAC is relevant to the occurrence of cancer (Archer, S. Y. etc. 1998 Proc. Nat. Acad. Sci. USA, 95: 6791-6796). When HDAC is over expressed, it will inhibit in vivo gene expression of natural tumor-inhibiting factors such as p53 (Gu, W. etc. 1997 Cell, 90: 595-606). However, inhibitors of HDAC (HDACi) enhance chromatin histone acetylation level, thus resulting in activation of expression of specific genes, accordingly resulting in differentiation of cells or apoptosis of cancer cells. Clinical studies show that the high level of acetylation of histones can be achieved by inhibiting the activity of HDAC.
The HDAC that have already been discovered at present can be divided into the following categories on the basis of structure: short-chain fatty acids; hydroxamic acids; electrophilic epoxy-ketons group; o-phenylenediamines and macrocyclic peptides (Miller, T. A. etc. 2003 J. Med. Chem. 46:5097; Rosato, R. R. etc. 2004 Expert. Opin. Invest. Drugs 13:21; Monneret, C., 2005 Eur. J. Med. 40:1; Yoo, C. B., etc. 2006 Nat. Rev. Drug Discovery 5:37). The HDACi structure-activity relationship studies have shown that most HDACis can be segmented into surface recognition structural domain, zinc chelating region (ZBG) and hydrophobic aliphatic chain connecting the former two parts (Marks, P. 2007 Oncogene 26:1351).
Histone deacetylase (HDAC) is an important protein for epigenetic regulation, which regulates chromatin remodeling, gene expression and functions of various proteins including transcription factors, histones, cytoskeletal proteins, etc. HDAC are a class of small molecule compounds that can block the activity of HDAC and lead to cell cycle arrest, cell differentiation and apoptosis, which is the reason why they have been applied in tumor therapy. Recent experimental results show that HDAC may also have anti-inflammatory and immunemodulatory effects. Camelo et al. found that in the mice model of MS (Experimental autoimmune encephalomyelitis, EAE) HDACi TSA can effectively inhibit T cell invasion to the central nervous system of mice, thereby reducing the clinical symptoms of the disease. Chung et al. found that, the HDAC is phenyl butyric acid and TSA can inhibit expression of TNF-alpha in animal arthritis models and reduce the infiltration of mononuclear cells, thereby reducing the symptoms of the disease. Studies carried out by Bosisio et al. proved that HDACi can inhibit the antigen-presenting dendritic cell from secreting cytokines in favor of producing TH1 and TH17, which includes IL-12, IL-23 etc. Studies carried out by Tao et al. showed that HDACi can enhance the differentiation of the suppressive Treg cell and inhibitory function on TH1 and TH17 cells. The above-mentioned studies showed that the inhibition of HDAC is closely related to the occurrence and development of autoimmune diseases. HDACi with lower toxicity, better selectivity will contribute to the treatment of autoimmune diseases, especially to the treatment of MS diseases.
Largazole is a highly functionalized sixteen-membered cyclic peptide lactone isolated from the Florida marine cyanobacteria Symploa sp. (Taori, K., etc. 2008 J. Am. Chem. Soc. 130:1806-1807; Ying, Y. et al. 2008 J. Am. Chem. Soc. 130:8455-8459), and its structure is shown as follows. Largazole has a novel skeleton structure, which includes: the tandem motif of dihydro-thiazole ring substituted by 4-methyl and thiazole ring, L-valine and (3S,4E)-3-hydroxy-7-sulfydryl-4-heptenoic acid. Pharmacological experiments show that largazole is able to selectively inhibit the growth of breast cancer cells (MDA-MB-231) and fibroblast osteosarcoma cells (U2OS), while showing less effect on normal mammary epithelial cells (NMuMG) and normal fibroblasts (NIH3T3). Later studies showed that largazole is able to selectively inhibit class I HDAC. Based on those knowledge of largazole, the inventors optimized and modified the structure of largazole, and evaluated their activities, thereby obtaining a series of compounds with potential for further development.
